Biology:Extracellular signal-regulated kinases

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Short description: Class of enzymes
Main page: Biology:Mitogen-activated protein kinase

In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.[citation needed]

The term, "extracellular signal-regulated kinases", is sometimes used as a synonym for mitogen-activated protein kinase (MAPK), but has more recently been adopted for a specific subset of the mammalian MAPK family.[citation needed]

In the MAPK/ERK pathway, Ras activates c-Raf, followed by mitogen-activated protein kinase kinase (abbreviated as MKK, MEK, or MAP2K) and then MAPK1/2 (below). Ras is typically activated by growth hormones through receptor tyrosine kinases and GRB2/SOS, but may also receive other signals. ERKs are known to activate many transcription factors, such as ELK1,[1] and some downstream protein kinases.

Disruption of the ERK pathway is common in cancers, especially Ras, c-Raf, and receptors such as HER2.

Mitogen-activated protein kinase 1

mitogen-activated protein kinase 1
Identifiers
SymbolMAPK1
Alt. symbolsPRKM2, PRKM1
NCBI gene5594
HGNC6871
OMIM176948
RefSeqNM_002745
UniProtP28482
Other data
LocusChr. 22 q11.2

Mitogen-activated protein kinase 1 (MAPK1) is also known as extracellular signal-regulated kinase 2 (ERK2). Two similar protein kinases with 85% sequence identity were originally called ERK1 and ERK2.[2] They were found during a search for protein kinases that are rapidly phosphorylated after activation of cell surface tyrosine kinases such as the epidermal growth factor receptor. Phosphorylation of ERKs leads to the activation of their kinase activity.

The molecular events linking cell surface receptors to activation of ERKs are complex. It was found that Ras GTP-binding proteins are involved in the activation of ERKs.[3] Another protein kinase, Raf-1, was shown to phosphorylate a "MAP kinase-kinase", thus qualifying as a "MAP kinase kinase kinase".[4] The MAP kinase-kinase, which activates ERK, was named "MAPK/ERK kinase" (MEK).[5]

Receptor-linked tyrosine kinases, Ras, Raf, MEK, and MAPK could be fitted into a signaling cascade linking an extracellular signal to MAPK activation.[6] See: MAPK/ERK pathway.

Transgenic gene knockout mice lacking MAPK1 have major defects in early development.[7] Conditional deletion of Mapk1 in B cells showed a role for MAPK1 in T-cell-dependent antibody production.[8] A dominant gain-of-function mutant of Mapk1 in transgenic mice showed a role for MAPK1 in T-cell development.[9] Conditional inactivation of Mapk1 in neural progenitor cells of the developing cortex lead to a reduction of cortical thickness and reduced proliferation in neural progenitor cells.[10]

Mitogen-activated protein kinase 3

mitogen-activated protein kinase 3
Identifiers
SymbolMAPK3
Alt. symbolsPRKM3
NCBI gene5595
HGNC6877
OMIM601795
RefSeqNM_001040056
UniProtP27361
Other data
LocusChr. 16 p11.2

Mitogen-activated protein kinase 3 (MAPK3) is also known as extracellular signal-regulated kinase 1 (ERK1). Transgenic gene knockout mice lacking MAPK3 are viable and it is thought that MAPK1 can fulfill some MAPK3 functions in most cells.[11] The main exception is in T cells. Mice lacking MAPK3 have reduced T cell development past the CD4+ and CD8+ stage.

Clinical significance

Activation of the ERK1/2 pathway by aberrant RAS/RAF signalling, DNA damage, and oxidative stress leads to cellular senescence.[12] Low doses of DNA damage resulting from cancer therapy cause ERK1/2 to induce senescence, whereas higher doses of DNA damage fail to activate ERK1/2, and thus induce cell death by apoptosis.[12]

References

  1. ↑ "elk-1 proteins interact with MAP kinases". Oncogene 9 (7): 1855–60. July 1994. PMID 8208531. 
  2. ↑ "Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies". Cell Regulation 2 (5): 357–71. May 1991. doi:10.1091/mbc.2.5.357. PMID 1654126. 
  3. ↑ "Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein". The EMBO Journal 11 (2): 569–74. February 1992. doi:10.1002/j.1460-2075.1992.tb05088.x. PMID 1371463. 
  4. ↑ "Raf-1 activates MAP kinase-kinase". Nature 358 (6385): 417–21. July 1992. doi:10.1038/358417a0. PMID 1322500. Bibcode: 1992Natur.358..417K. 
  5. ↑ "Purification of a murine protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product: relationship to the fission yeast byr1 gene product". Proceedings of the National Academy of Sciences of the United States of America 89 (17): 8205–9. September 1992. doi:10.1073/pnas.89.17.8205. PMID 1381507. Bibcode: 1992PNAS...89.8205C. 
  6. ↑ "A protein factor for ras p21-dependent activation of mitogen-activated protein (MAP) kinase through MAP kinase kinase". Proceedings of the National Academy of Sciences of the United States of America 90 (3): 975–9. February 1993. doi:10.1073/pnas.90.3.975. PMID 8381539. Bibcode: 1993PNAS...90..975I. 
  7. ↑ "Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation". Proceedings of the National Academy of Sciences of the United States of America 100 (22): 12759–64. October 2003. doi:10.1073/pnas.2134254100. PMID 14566055. Bibcode: 2003PNAS..10012759Y. 
  8. ↑ Sanjo, Hideki; Hikida, Masaki; Aiba, Yuichi; Mori, Yoshiko; Hatano, Naoya; Ogata, Masato; Kurosaki, Tomohiro (2007). "Extracellular signal-regulated protein kinase 2 is required for efficient generation of B cells bearing antigen-specific immunoglobulin G". Molecular and Cellular Biology 27 (4): 1236–1246. doi:10.1128/MCB.01530-06. ISSN 0270-7306. PMID 17145771. 
  9. ↑ Sharp, L. L.; Schwarz, D. A.; Bott, C. M.; Marshall, C. J.; Hedrick, S. M. (1997). "The influence of the MAPK pathway on T cell lineage commitment". Immunity 7 (5): 609–618. doi:10.1016/s1074-7613(00)80382-9. ISSN 1074-7613. PMID 9390685. 
  10. ↑ Samuels, Ivy S.; Karlo, J. Colleen; Faruzzi, Alicia N.; Pickering, Kathryn; Herrup, Karl; Sweatt, J. David; Saitta, Sulagna C.; Landreth, Gary E. (2008-07-02). "Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function". The Journal of Neuroscience 28 (27): 6983–6995. doi:10.1523/JNEUROSCI.0679-08.2008. ISSN 1529-2401. PMID 18596172. 
  11. ↑ "Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice". Science 286 (5443): 1374–7. November 1999. doi:10.1126/science.286.5443.1374. PMID 10558995. 
  12. ↑ 12.0 12.1 "Regulation of senescence traits by MAPKs". GeroScience 42 (2): 397–408. 2020. doi:10.1007/s11357-020-00183-3. PMID 32300964. 

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